Despite significant advances in the treatment of cardiovascular disease over the past several decades, therapeutic approaches to prevent the pathologic myocardial remodeling processes that lead to heart failure, a worldwide health threat, are limited. Evidence is emerging that mitochondrial dysfunction contributes to the pathogenesis of heart failure. We have shown that the transcriptional coactivators, PPAR? transcriptional coactivator-1alpha and beta (PGC-1? and PGC-1?), are required for normal perinatal mitochondrial biogenesis and respiratory function in heart. The expression and activity of PGC-1? and several of its transcription factor targets (PPAR?, ERR?), are diminished in pathologic forms of cardiac hypertrophy and in the failing heart. Recent findings suggest that chronic deactivation of PGC-1 signaling becomes maladaptive, leading to mitochondrial dysfunction and heart failure. However, the specific PGC-1 target genes and pathways, relevant to progressive energy metabolic demise and contractile dysfunction in the failing heart remain unknown. This proposal is designed to test the hypothesis that dysregulated activity of processes downstream of PGC-1? and PGC-1? lead to mitochondrial dysfunction and contribute to the pathologic remodeling that leads to heart failure. It is also proposed that downregulation of a subset of PGC-1 targets, including those involved in fuel preference shifts, may be protective in the context of pathophysiological stress. To address this problem, we have assembled a multi-disciplinary team to use a systems approach, combining unbiased gene transcriptional and targeted, mass spectrometric-based metabolite profiling. The objective of Aim 1 will be to identify relevant dysregulated genes and altered metabolite profiles in the hearts of an inducible, cardiac-specific, PGC-1?/? loss-of-function mouse model of heart failure. In Aim 2, the dataset in Aim 1 will be compared with that generated for mice that have been genetically-engineered to model derangements in mitochondrial fuel burning, including selective blocks in mitochondrial FA and glucose oxidation, but normal cardiac function. In Aim 3, genomic and metabolomic profiling will be conducted with hearts of wild-type mice with: 1) physiologic (exercise-induced) cardiac hypertrophy; 2) compensated pathologic cardiac hypertrophy; and 3) decompensated cardiac hypertrophy (failing heart). Informatic-based comparative analysis of the datasets from Aims 1-3 will be used to generate a prioritized list of genes, metabolites, and corresponding metabolic pathways/processes that will serve as candidate signatures for mitochondrial derangements relevant to the development of pathologic cardiac metabolic and functional remodeling, to be further validated in Aim 4. The long-term goal of this project is to evaluate the efficacy of modulating the candidate pathways to maintain cardiac mitochondrial function as a new therapeutic approach for the prevention and treatment of heart failure. (End of Abstract)